Five years after escaping from the U.S., Dominic Toretto and his new crew, consisting of his girlfriend Letty, Tego Leo, Rico Santos, Cara and Han Lue, are hijacking fuel tankers in the Dominican Republic. Dominic suspects that the police are on their trail, forcing the crew to disband and go their separate ways, with Han deciding to go to Tokyo. Realizing that he must leave, Dominic runs, leaving Letty behind to protect herself from harm.
Three months later, Dominic is now residing in Panama City. He gets a call from his sister, Mia Toretto, who tells him that Letty has been murdered. Dominic heads back to Los Angeles to attend her funeral and examine the crash and finds traces of nitromethane on the ground. He visits the only car mechanic that sells nitromethane in LA and forces him into giving him the name David Park, the man who ordered the fuel, and informs him that the only car that uses nitromethane in the area is a green 1972 Ford Gran Torino Sport.
Meanwhile, FBI agent Brian O’Conner is trying to track down a Mexican drug lord, Arturo Braga. His search leads him to David Park, and he tracks him down using an illegal modification record on his car. Dominic arrives at Park’s apartment first and hangs him out of the window by his ankles before Brian arrives. Brian saves Park and Park becomes the FBI’s new informant. Park gets Brian into a street race. Brian selects a modified 2002 Nissan Skyline GT-R R34 from the impound lot. Dominic races in his modified 1970 Chevrolet Chevelle SS. Gisele Yashar, the liaison for Braga, reveals that the winner will become the last driver on a team that traffics heroin between the Mexico–United States border. Dominic wins by bumping Brian’s car while it is in nitro, making him lose control. Brian uses his power as an FBI agent to arrest another driver, Dwight Mueller, and takes his place on the team.
The team meets up with Braga’s personal henchman, Fenix, and Dominic notices that Fenix drives the same Torino the mechanic described. They drive across the border using tunnels to avoid detection. Dominic confronts Fenix and learns that he himself killed Letty when she tried to escape him. A stand-off ensues, though not before Dominic creates a diversion by loosening his car with nitrous—sparking a vehicle explosion that destroys his car and several others, including Brian’s. In the ensuing chaos, Dominic and Brian hijack a 1999 Hummer H1 with $60 million worth of heroin in it. Dominic and Brian drive back to LA and hide the heroin in a police impound lot, where Brian picks up a modified Subaru Impreza WRX STI Hatchback; they subsequently drive back to Dominic’s house, where they reunite with Mia.
Dominic finds out Brian was the last person to have contact with Letty, which results in Dominic attacking Brian until he explains that Letty was working undercover—she was tracking down Braga in exchange for clearing Dominic’s record. Brian tells his superiors that in exchange for Dominic’s pardon, he will lure Braga into a trap, forcing him to show up to exchange money for the heroin. At the drop site, the man who claims to be “Braga” is revealed as a decoy, and “Campos”—the real Braga—escapes with Fenix and the pair flee to Mexico. In the ensuing chaos, Fenix nearly runs over Gisele, before Dom saves her.
Brian and Dominic travel to Mexico to catch Braga, with the help of Gisele, who gives them directions as a favor in return for Dom saving her life. Brian and Dom find him at a church and apprehend him. As Braga’s henchmen try to rescue him, Brian and Dominic drive through the tunnels back to the United States. Brian crashes his car after taking fire from Braga’s men. He is then injured after being T-boned by Fenix. Before Fenix can kill Brian, Dominic drives into and kills Fenix in retaliation for Letty’s death. As police and helicopters approach the crash site on the American side of the border, Brian tells Dominic to leave, but Dominic refuses—saying he is not running anymore. Despite Brian’s request for clemency, the judge sentences Dominic to 25 years to life.
Brian resigns from the FBI and Dominic boards a prison bus that will transport him to Lompoc penitentiary. As the bus drives down the road, Brian, Mia, Leo, and Santos arrive in their cars to intercept it.